Should linezolid (Zyvox) doses be adjusted for kidney function?
Linezolid (Zyvox) is an oxazolidinone antibiotic that can be used for the treatment of infections caused by drug-resistant organisms such as MRSA and VRE. In recent years, linezolid has garnered more attention due to reduced concerns from some toxicities (read about serotonin syndrome risk here) as well as falling prices (especially the oral formulation). As interest in linezolid has increased, one debate that has emerged from the literature is whether it should ever be dose adjusted for renal function.
According to the linezolid package insert, total clearance of linezolid is 65% by nonrenal, under steady-state ~30% of the dose appears in the urine as linezolid, and mean renal clearance of linezolid is 40 mL/min which suggests net tubular reabsorption. For patients with renal impairment, the package insert does not recommend linezolid dose adjustments, stating the parent drug (linezolid) is unaltered by any degree of renal impairment. However, the two primary metabolites of linezolid (named metabolite A and metabolite B) do accumulate with renal impairment. The package inset states that in patients with renal dysfunction, it is a risk:benefit decision of whether linezolid is reasonable to use.
An important part of this discussion is that there appears to be greater risk of linezolid-associated thrombocytopenia when it is used in patients who have renal insufficiency. In 2019 Crass and colleagues investigated linezolid-associated thrombocytopenia by combining an observational toxicity analysis with therapeutic drug monitoring data. They found that renal impairment was an independent risk factor for linezolid associated thrombocytopenia. The rate of thrombocytopenia was double for patients with renal dysfunction (43% vs 17%). To take it a step further, the investigators analyzed the relationship between dosing and achieving adequate drug levels to kill bacteria and treat the infection. Using that therapeutic drug monitoring data, they found renal function impacted linezolid clearance and that dose reductions in patients with an eGFR below 60 mL/min improved optimal drug levels. This led them to conclude that therapeutic drug monitoring may be helpful for linezolid and that dose reductions may have a role when renal dysfunction was present.
In 2017, Pea and colleagues retrospectively evaluated a single hospital’s 10-year experience with linezolid therapeutic drug monitoring. They found a creatinine clearance below 40 mL/min was strongly associated with linezolid overexposure while a creatinine clearance above 100 mL/min was strongly associated with linezolid under-exposure.
In 2022, Liu and colleagues conducted a systematic review and meta-analysis of 27 and 25 studies respectively, suggesting that the evaluated literature supports the claim that a decrease in renal function correlates with an increased risk of thrombocytopenia due to overexposure to linezolid.
Not all studies have found renal failure to be associated with linezolid-induced thrombocytopenia and it can happen in patients without renal impairment. For example an observational study by Moraza et al from 2015 found that hematological toxicity (most commonly neutropenia or thrombocytopenia) during linezolid use was not associated with renal failure. Veerman and colleagues published a retrospective study in 2023 which included 78 patients without renal impairment who were treated for bone and joint infections. They found 20 patients stopped therapy due to toxicity, most often gastrointestinal intolerance (42%) and malaise (32%). For the 67 patients that received linezolid beyond 28 days, 87% completed therapy as scheduled. Severe cytopenia was observed in four patients and was reversible after linezolid discontinuation. One patient suffered optic neuropathy related to linezolid exposure. None of the patients required linezolid to be stopped prematurely due to cytopenias.
Unlike treating a VRE or MRSA infection, attempting to limit toxicity risk by reducing the dose of linezolid (e.g., to 600 mg or 300 mg daily) is a common practice when treating multidrug-resistant tuberculosis. Use of pyridoxine to mitigate thrombocytopenia in this setting has been proposed but not found to be effective. Unfortunately even with lower doses, toxicities are still encountered.
For those considering a renal adjustment of linezolid, beware that there may be some operational challenges. For example, the 600 mg tablets are not scored which makes them difficult to break in half. They can however be crushed and are rapidly absorbed upon oral administration, which is notable. There is an oral solution formulation, but that tends to be much more costly than the oral tablet. The IV linezolid formulation has some different dose options, but the premixed 600 mg IV dose is fairly common and one of the big benefits of linezolid is its excellent oral absorption and bioavailability, making the IV option less appealing (especially if that means home infusion). Finally the usual dose of linezolid is so easy to remember at 600 mg IV or PO BID in adults, sporadically giving augmented doses may lead to confusion with the medical, nursing, or pharmacy team.
Ultimately, like all things in infectious diseases, the answer is a case-based decision. The risks and benefits must be weighed against each other to determine a reasonable course of action at that time.
REFERENCES & READINGS
- Green S, Tsai YV. Precision Dosing of Linezolid: Therapeutic Drug Monitoring in To-Marrow. Contagion Live. 2022.
- Abdul-Aziz MH, Alffenaar JC, Bassetti M, et al. Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper. Intensive Care Med. 2020;46(6):1127-1153. doi:10.1007/s00134-020-06050-1.
- Crass RL, Cojutti PG, Pai MP, Pea F. Reappraisal of Linezolid Dosing in Renal Impairment To Improve Safety. Antimicrob Agents Chemother. 2019;63(8):e00605-19. Published 2019 Jul 25. doi:10.1128/AAC.00605-19.
- Cattaneo D, Gervasoni C, Cozzi V, Castoldi S, Baldelli S, Clementi E. Therapeutic drug management of linezolid: a missed opportunity for clinicians? Int J Antimicrob Agents. 2016 Dec;48(6):728-731. doi: 10.1016/j.ijantimicag.2016.08.023.
- Pea F, et al. A 10-Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital-wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients? BCPT. 2017.
- Liu X, et al. Safety of linezolid in patients with decreased renal function and trough monitoring: a systematic review and meta-analysis. BMC Pharmacol Toxicol. 2022; 23: 89.
- Moraza L et al. Linezolid-induced haematological toxicity. Farm Hosp. 2015.
- Veerman K, et al. Prolonged use of linezolid in bone and joint infections: a retrospective analysis of adverse effects. JAC. 2023.
- Srivastava S, et al. Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis. AAC. 2017
- Plachouras D, et al. No effect of pyridoxine on the incidence of myelosuppression during prolonged linezolid treatment. CID. 2006.
- Wasserman S. Linezolid in the treatment of drug-resistant tuberculosis: the challenge of its narrow therapeutic index. Expert Rev Anti Infect Ther. 2016 Oct;14(10):901-15.
- Rao GG, et al. Therapeutic Drug Monitoring Can Improve Linezolid Dosing Regimens in Current Clinical Practice: A Review of Linezolid Pharmacokinetics and Pharmacodynamics. There Drug Monit. 2020. Feb;42(1):83-92.
- Kawassuji H, et al. Proposal of initial and maintenance dosing regimens with linezolid for renal impairment patients. BMC Pharmacy Tox. 2021 Mar 4;22(1):13.
The ID PharmD Q&A pages attempt to answer common pharmacy questions by providing the perspective and opinion of a trained expert with knowledge relevant to the question. That noted, these answers are not provided as all-inclusive comprehensive responses. This is not provided for direct patient care purposes.